Electrogram morphology-based CRT optimization

ABSTRACT

A method and system for determining an optimum atrioventricular delay (AVD) interval and/or ventriculo-ventricular delay (VVD) intervals for delivering ventricular resynchronization pacing in an atrial tracking or atrial sequential pacing mode. Evoked response electrograms recorded at different AVD and VVD intervals are used to determine the extent of paced and intrinsic activation.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/097,460, filed Apr. 1, 2005, now issued as U.S. Pat. No. 7,555,340,which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This patent application pertains to methods and apparatus for thetreatment of cardiac disease. In particular, it relates to methods andapparatus for improving cardiac function with resynchronization therapy.

BACKGROUND

Implantable devices that provide electrical stimulation to selectedchambers of the heart have been developed in order to treat a number ofcardiac disorders. A pacemaker, for example, is a device which paces theheart with timed pacing pulses, most commonly for the treatment ofbradycardia where the ventricular rate is too slow. Atrio-ventricularconduction defects (i.e., AV block) and sick sinus syndrome representthe most common causes of bradycardia for which permanent pacing may beindicated. If functioning properly, the pacemaker makes up for theheart's inability to pace itself at an appropriate rhythm in order tomeet metabolic demand by enforcing a minimum heart rate. Implantabledevices may also be used to treat cardiac rhythms that are too fast,with either anti-tachycardia pacing or the delivery of electrical shocksto terminate atrial or ventricular fibrillation.

Implantable devices have also been developed that affect the manner anddegree to which the heart chambers contract during a cardiac cycle inorder to promote the efficient pumping of blood. The heart pumps moreeffectively when the chambers contract in a coordinated manner, a resultnormally provided by the specialized conduction pathways in both theatria and the ventricles that enable the rapid conduction of excitation(i.e., depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Patients who exhibit pathology of these conduction pathways,such as bundle branch blocks, can thus suffer compromised pumpingperformance.

Heart failure refers to a clinical syndrome in which an abnormality ofcardiac function causes a below normal stroke volume that can fall belowa level adequate to meet the metabolic demand of peripheral tissues. Itusually presents as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies with ischemic heart disease being the mostcommon. Some heart failure patients suffer from some degree of AV blockor are chronotropically deficient such that their cardiac output can beimproved with conventional bradycardia pacing. Such pacing, however, mayresult in some degree of uncoordination in atrial and/or ventricularcontractions because pacing excitation from a single pacing site isspread throughout the myocardium only via the much slower conductingmuscle fibers of either the atria or the ventricles, and not thespecialized conduction pathways. Most pacemaker patients can stillmaintain more than adequate cardiac output with artificial pacing, butthe diminishment in pumping efficiency may be significant in a heartfailure patient whose cardiac output is already compromised.Intraventricular and/or interventricular conduction defects are alsocommonly found in heart failure patients and can contribute to cardiacdysfunction by causing unsynchronized contractions during intrinsicbeats.

In order to treat these problems, implantable cardiac devices have beendeveloped that provide appropriately timed electrical stimulation to oneor more heart chambers in an attempt to improve the coordination ofatrial and/or ventricular contractions, termed cardiac resynchronizationtherapy (CRT). Currently, a most common form of CRT applies stimulationpulses in either a left ventricle-only pacing mode or a biventricularpacing mode, where the pace or paces are delivered after a programmedatrio-ventricular (AV) delay interval with respect to the detection anintrinsic atrial contraction or delivery of an atrial pace. In the caseof biventricular pacing, a first pace to one ventricle is deliveredafter the AV delay interval, and a second pace to the contralateralventricle is then delivered after a specified ventriculo-ventricular(VV) delay interval with respect to the first pace. Appropriatespecification of these parameters is necessary in order to achieve thedesired optimum coordination between the atria and the ventricles andwithin the ventricles.

SUMMARY

The present disclosure relates to methods and apparatus for deliveringcardiac resynchronization therapy (CRT) in which an evoked responseelectrogram is recorded during one or more cardiac cycles and used todetermine an optimum AV delay interval and/or VV delay interval fordelivering CRT and/or to monitor the effectiveness of such therapy. Theoptimum AV delay interval may be regarded as one which results in acoincidence of paced and intrinsic cardiac activity in a patient withintact native AV conduction. In a particular embodiment for optimizingthe AV delay interval, an evoked response electrogram is recorded duringa paced cardiac cycle using a short AV delay interval such that nointrinsic activation of the ventricles occurs. The AV delay interval isthen incremented during subsequent cardiac cycles until intrinsicactivation occurs, as revealed by a morphology analysis of the recordedevoked response electrogram. Intrinsic activation may be detected whenthe morphology of the evoked response electrograms recorded with theshort and incremented AV delay intervals differs by a specified amount.In another embodiment, the VV delay interval is also optimized bytesting a range of VV delay values, where the optimum AV and VV delayinterval values are selected as those which produce the desiredmorphology in the evoked response waveform.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of evoked response electrograms showing pacedactivation only and fusion of paced and intrinsic activation.

FIG. 2 is a system diagram of an exemplary CRT device.

FIG. 3 illustrates an exemplary algorithm for computing an optimum AVDinterval.

DETAILED DESCRIPTION

As described above, cardiac resynchronization therapy is pacingstimulation applied to one or more heart chambers in a manner thatcompensates for conduction delays. Ventricular resynchronization pacingis useful in treating heart failure in patients with interventricular orintraventricular conduction defects because, although not directlyinotropic, resynchronization results in a more coordinated contractionof the ventricles with improved pumping efficiency and increased cardiacoutput. Ventricular resynchronization can be achieved in certainpatients by pacing at a single unconventional site, such as the leftventricle instead of the right ventricle in patients with leftventricular conduction defects. Resynchronization pacing may alsoinvolve biventricular pacing with the paces to right and left ventriclesdelivered either simultaneously or sequentially, with the intervalbetween the paces termed the VV delay (VVD) interval (also sometimesreferred to as the LV offset (LVO) interval or biventricular offset(BVO) interval). The VV delay interval may be zero in order to pace bothventricles simultaneously, or non-zero in order to pace the left andright ventricles sequentially. As the term is used herein, a negativeVVD refers to pacing the left ventricle before the right, while apositive VVD refers to pacing the right ventricle first.

Cardiac resynchronization therapy is most conveniently delivered inconjunction with a bradycardia pacing mode. Bradycardia pacing modesrefer to pacing algorithms used to pace the atria and/or ventricles in amanner that enforces a certain minimum heart rate. Because of the riskof inducing an arrhythmia with asynchronous pacing, most pacemakers fortreating bradycardia are programmed to operate synchronously in aso-called demand mode where sensed cardiac events occurring within adefined interval either trigger or inhibit a pacing pulse. Inhibiteddemand pacing modes utilize escape intervals to control pacing inaccordance with sensed intrinsic activity. In an inhibited demand mode,a pacing pulse is delivered to a heart chamber during a cardiac cycleonly after expiration of a defined escape interval during which nointrinsic beat by the chamber is detected. For example, a ventricularescape interval for pacing the ventricles can be defined betweenventricular events, referred to as the cardiac cycle (CC) interval withits inverse being the lower rate limit or LRL. The CC interval isrestarted with each ventricular sense or pace. In atrial tracking and AVsequential pacing modes, another ventricular escape interval is definedbetween atrial and ventricular events, referred to as the AV delay (AVD)interval, where a ventricular pacing pulse is delivered upon expirationof the AV delay interval if no ventricular sense occurs before. In anatrial tracking mode, the atrio-ventricular pacing delay interval istriggered by an atrial sense and stopped by a ventricular sense or pace.An atrial escape interval can also be defined for pacing the atriaeither alone or in addition to pacing the ventricles. In an AVsequential pacing mode, the atrio-ventricular delay interval istriggered by an atrial pace and stopped by a ventricular sense or pace.Atrial tracking and AV sequential pacing are commonly combined so thatan AVD interval starts with either an atrial pace or sense. As the termis used herein for biventricular pacing, the AVD interval refers to theinterval between an atrial event (i.e., a pace or sense in one of theatria, usually the right atrium) and the first ventricular pace whichpre-excites one of the ventricles, and the pacing instant for thenon-pre-excited ventricle is specified by the VVD interval so that it ispaced at an interval AVD+VVD after the atrial event. With eitherbiventricular or left ventricle-only pacing, the AVD interval may be thesame or different depending upon whether it is initiated by an atrialsense or pace (i.e., in atrial tracking and AV sequential pacing modes,respectively). A common way of implementing biventricular pacing or leftventricle-only pacing is to base the timing upon only right ventricularactivity so that ventricular escape intervals are reset or stopped byright ventricular senses.

For optimum hemodynamic performance, it is desirable to deliverventricular pacing, whether for resynchronization pacing or conventionalbradycardia pacing, in an atrial tracking and/or AV sequential pacingmode in order to maintain the function of the atria in pre-loading theventricles (sometimes referred to atrio-ventricular synchrony). Sincethe objective of CRT is to improve a patient's cardiac pumping function,it is therefore normally delivered in an atrial-tracking and/or AVsequential mode and requires specification of an AVD interval (and, inthe case of biventricular pacing, a VVD interval) which, ideally,results in the ventricles being synchronized during systole after beingoptimally preloaded during atrial systole. That is, both optimalinterventricular synchrony and optimal atrio-ventricular synchrony areachieved.

Cardiac resynchronization therapy is most commonly applied in thetreatment of patients with heart failure due to left ventriculardysfunction which is either caused by or contributed to by leftventricular conduction abnormalities such as left bundle branch block.(More rarely, some patients have a right ventricular conduction deficitsuch as right bundle branch block and require pre-excitation of theright ventricle in order achieve synchronization of their ventricularcontractions.) In patients with a left ventricular conduction deficit,the left ventricle or parts of the left ventricle contract later thannormal during systole which thereby impairs pumping efficiency. In orderto resynchronize ventricular contractions in such patients, pacingtherapy is applied such that the left ventricle or a portion of the leftventricle is pre-excited relative to when it would become depolarized inan intrinsic contraction. Optimal pre-excitation of the left ventriclein a given patient may be obtained with biventricular pacing or withleft ventricular-only pacing by pre-exciting the left ventricle with apace delivered to the left ventricle which excites the left ventricularfree wall. The desired situation is simultaneous contraction of the leftventricular free wall and ventricular septum (septum-free wall fusion).The excitation of the ventricular septum may be a result of eitherintrinsic activation from the AV node or a pace delivered to the rightventricle. If intrinsic AV conduction to the right ventricle is normal,intrinsic activation of the ventricular septum occurs at an intervalfollowing an atrial contraction which produces optimal pre-loading ofthe ventricles during atrial systole. Therefore, in a patient withnormal intrinsic AV conduction to the right ventricle but with a leftventricular conduction deficit, the hemodynamically optimum AVD intervalfor pre-exciting the left ventricle is one which results in the leftventricular free wall contracting due to the pace at the same time thatthe ventricular septum is contracting due to intrinsic activation. Thissituation may be brought about by pre-exciting the left ventricle at theoptimum AVD interval with either left ventricle-only or biventricularpacing. In the latter case, depending upon the implementation, the rightventricular pace scheduled to occur at the VVD interval followingexpiration of the AVD interval may either be inhibited by the intrinsicright ventricular activation, occur coincidently with the rightventricular activation, or occur after intrinsic right ventricularactivation during the refractory period.

In the case of a patient without intact intrinsic AV conduction, leftventricle-only pacing would produce a ventricular contraction in whichdepolarization spreads only from the left ventricular pacing site. Itmay therefore be desirable to deliver paces to both ventricles in abiventricular pacing mode in order to produce a more hemodynamicallyeffective contraction. The minimum pacing rate would normally then beset to a value which results in only paced cycles. That is, anyintrinsic activation due to an idioventricular rhythm would occur at tooslow a rate to inhibit paces. The AV delay and VV delay intervals arethen set to values which provide atrio-ventricular and interventricularsynchrony. If, however, the patient does not have complete AV block,such that intrinsic activation of either ventricle may occurintermittently, it may be desirable to utilize biventricular pacing andto set the AV delay and VV delay intervals to values which producefusion beats when intrinsic conduction to the ventricles occurs. Forexample, in a patient with a left ventricular conduction deficit andintermittent AV block to the right ventricle, pre-excitation of the leftventricle with an optimum AV delay intervals would produce a fusion beatwhen intrinsic conduction to the right ventricle occurs which results inthe left ventricular free wall contracting due to the pace at the sametime that the ventricular septum is contracting due to intrinsicactivation. The optimum VV delay in this case would then be a value longenough to so that the right ventricular pace subsequent to the leftventricular pace is inhibited by the intrinsic right ventricularactivation (or is delivered when the right ventricle is refractory) butshort enough to produce a hemodynamically effect beat when no intrinsicAV conduction to the right ventricle occurs.

As discussed above, in a patient with normal intrinsic AV conduction tothe right ventricle and a left ventricular conduction deficit, thedesired result of CRT is a fusion beat such that the left ventricularpace causes contraction of the left ventricular free wall at the sametime intrinsic conduction from the AV node causes contraction of theventricular septum. Such a fusion beat may be recognized in an evokedresponse electrogram. An electrogram is a signal showing the amplitudeand time course of cardiac depolarization and repolarization as recordedby either internal or external electrodes, the latter referred to as asurface EKG. An evoked response electrogram is one recorded during apaced cardiac cycle. Since the depolarization and repolarizationpatterns in the ventricles are different for paced and intrinsicactivation, electrograms recorded during paced, intrinsically activated,and fusion beats are morphologically distinguishable. FIG. 1 shows arepresentation of an evoked response electrograms 101 recorded during acardiac cycle when both ventricles are activated by a pace delivered tothe left ventricle with no intrinsic activation, i.e., a purely pacedbeat. Purely paced beats can occur with left ventricle-only pacing whenthe left ventricular pace is delivered early enough that thedepolarization spreads to and excites the right ventricle beforeintrinsic activation occurs. In the case of biventricular pacing with anegative VV delay interval, an evoked response electrogram may representa purely paced beat or a fusion beat in which the left ventricle ispaced but the right ventricle is intrinsically activated with the rightventricular pace being inhibited. A purely paced beat in this situationmay occur with spread of excitation from the left ventricular pace or byboth the right ventricular and left ventricular paces capturing theheart before intrinsic activation. The desired optimal situation fortreating left ventricular conduction disorders with CRT in patients withat least some degree of normal AV conduction, however, is a fusion beatwhere the left ventricle is excited by the left ventricular pace whilethe right ventricle is intrinsically activated by conduction from the AVnode. Such a fusion beat is represented by evoked response electrograms103 for the case of left ventricle-only pacing. Since the morphologiesof electrograms 101 and 103 are different, it is possible to distinguishbetween purely paced beats and fusion beats by comparing theelectrograms or particular features derived therefrom.

The difference in morphologies of evoked response electrograms may beemployed by a system to compute optimal settings for the AV delay and VVdelay parameters for resynchronization pacing, i.e., intervals whichresult in the desired fusion beats. An exemplary computation method fordetermining an optimum AV delay interval is as follows. First, an evokedresponse electrogram is recorded during a cardiac cycle in which aventricular resynchronization pace (either a biventricular or leftventricle-only pace) is delivered at an AVD interval selected to beshort enough so that paced excitation of both ventricles occurs beforeintrinsic activation. The short AVD electrogram, or an average of suchelectrograms, may then be used as a purely paced reference waveform withwhich to compare electrograms recorded during subsequent paced cycleswith longer AVD intervals to determine when a fusion beat occurs. TheAVD interval can thus be gradually incremented until a fusion beatoccurs, at which point the optimum AV delay interval is found. A fusionbeat may be detected when there is a sufficient change in the evokedresponse electrogram as compared to the purely paced reference waveform.Whether a sufficient change has occurred may be determined bycross-correlating the evoked response electrogram with the purely pacedreference waveform and comparing the resulting correlation coefficientwith a predetermined threshold value. Alternatively, a particularfeature may be extracted from both the evoked response electrogramwaveform and the reference waveform, with the difference between theextracted features then compared to a threshold value. Examples of suchfeatures which may be extracted and compared include peak amplitudes,time intervals between particular identifiable points in the electrogramwaveforms, and computed functions of the electrogram waveforms.

In an alternative embodiment, an evoked response electrogram is recordedduring a cardiac cycle in which a ventricular resynchronization pace(either a biventricular or left ventricle-only pace) is delivered at anAVD interval selected to be long enough so that both ventricles areintrinsically activated. The long AVD electrogram, or an average of suchelectrograms, may then be used as an intrinsic reference waveform withwhich to compare electrograms recorded during subsequent paced cycleswith shorter AVD intervals to determine when a fusion beat occurs. TheAVD interval is gradually decremented until a fusion beat occurs, atwhich point the optimum AV delay interval is found. Similar to theprevious embodiment, a fusion beat is detected when there is asufficient change in the evoked response electrogram as compared to theintrinsic reference waveform.

A separate optimum AVD interval may be computed as described above forAVD intervals initiated by an atrial pace and for AVD intervalsinitiated by an atrial sense. Also, separate optimum AVD intervals maybe computed for different atrial rates in order to track thephysiological varying of the intrinsic AV interval with heart rate. Theatrial rate in a normal individual increases in response to increasedmetabolic demand or emotional excitement due to hormonal and neuralinfluences, the latter being increased sympathetic discharge relative toparasympathetic discharge. The neural and hormonal influencesresponsible for the increased heart rate also increase the force ofcardiac contractions and decrease the intrinsic AV interval since theventricles need to be filled more rapidly during a shorter diastole ifcardiac output is to be increased. Separate optimum AVD intervals mayalso be computed for atrial rates as a result of atrial pacing. Theoptimum AVD interval may also vary as a function of pacing pulse energy(i.e., pulse amplitude and/or pulse width). An empirically derivedlook-up table or other mapping function can be employed by theimplantable device to map particular atrial rates and/or pacing pulseenergies to different programmed optimum AVD intervals.

In the case of biventricular pacing, an optimum VV delay interval forproducing fusion beats may also determined by varying the VV delayinterval as evoked response electrograms are recorded and comparing theevoked response electrogram with a reference electrogram to determinewhen a fusion beat occurs. In one embodiment, an optimum AV delayinterval is first determined by the techniques described above usingleft ventricle-only pacing or biventricular pacing with a long VV delay.Next, biventricular pacing is delivered with a short VV delay so as toproduce beats with biventricular capture which can be used as a purelypaced reference electrogram waveform. The VV delay is then graduallylengthened until a fusion beat is detected by comparing the evokedresponse electrogram with the reference waveform in the same manner asdiscussed earlier. At that point, the optimum VV delay interval isfound. In an alternative embodiment, a long VV delay is used to generatea fusion beat reference. An initially long VV delay is then graduallyshortened until sufficient change evidencing a purely paced beat occurs,at which point the optimum VV delay interval is found. In anotherembodiment, multiple sites of the left ventricle are pre-excited withpacing pulses delivered at separate VV delay intervals. Optimum VV delayintervals may be found for each of the multiple pacing sites usingeither the incremented or decremented VV delay interval approach as justdescribed above.

The techniques for computing optimum AVD and VVD intervals as describedabove may be implemented in a number of different ways. In oneimplementation, a system for setting the pacing parameters includes anexternal programmer and an implantable device. The external programmercommands the implantable device to vary the AVD and/or VVD intervals asdescribed while electrogram signals generated by the sensing channels ofthe implantable device are transmitted to the external programmer via awireless telemetry link. The external programmer then computes theoptimum AVD and/or VVD intervals by detecting fusion beats. In anautomated system, the external programmer then automatically programsthe implantable device with the computed optimum AVD and/or VVD intervalvalue or values, while in a semi-automated system the externalprogrammer presents the computed optimum values to a clinician in theform of a recommendation. An automated system may also be made up of theimplantable device alone which is programmed to vary the AVD and/or VVDintervals, record evoked response electrograms in order to detect fusionbeats, and then automatically set the AVD and/or VVD intervals to thedetermined optimum value or values. In another embodiment, which may bereferred to as a manual system, the external programmer presents therecorded evoked response electrograms to a clinician for comparison anddetermination of the optimum AVD and/or VVD interval values. Unlessotherwise specified, references to a system for computing or settingpacing parameters throughout this document should be taken to includeany of the automated, semi-automated, or manual systems just described.

A description of an exemplary cardiac rhythm management device suitablefor delivering CRT therapy and recording evoked response electrograms isset forth below. The techniques for optimizing and monitoring CRTperformance discussed above may be implemented by appropriateprogramming of the device's controller.

1. Exemplary Device Description

Cardiac rhythm management devices such as pacemakers and ICDs aretypically implanted subcutaneously on a patient's chest and have leadsthreaded intravenously into the heart to connect the device toelectrodes used for sensing and delivery of electrical stimulation suchas defibrillation shocks and pacing pulses. A programmable electroniccontroller causes the delivery of pacing pulses in response to lapsedtime intervals and sensed electrical activity (i.e., intrinsic heartbeats not as a result of a pacing pulse). Pacemakers sense intrinsiccardiac electrical activity by means of internal electrodes disposednear the chamber to be sensed. A depolarization wave associated with anintrinsic contraction of the atria or ventricles that is detected by thepacemaker is referred to as an atrial sense or ventricular sense,respectively. In order to cause such a contraction in the absence of anintrinsic beat, a pacing pulse (either an atrial pace or a ventricularpace) with energy above the capture threshold must be delivered to thechamber.

A system diagram of an exemplary cardiac rhythm management device fordelivering cardiac resynchronization therapy is illustrated in FIG. 2.The controller of the device is made up of a microprocessor 10communicating with a memory 12, where the memory 12 may comprise a ROM(read-only memory) for program storage and a RAM (random-access memory)for data storage. The controller could be implemented by other types oflogic circuitry (e.g., discrete components or programmable logic arrays)using a state machine type of design, but a microprocessor-based systemis preferable. The controller is capable of operating the device in anumber of programmed modes where a programmed mode defines how pacingpulses are output in response to sensed events and expiration of timeintervals. A telemetry interface 80 is provided for communicating withan external programmer 300. The external programmer is a computerizeddevice with a controller 330 that can interrogate the device and receivestored data as well as adjust various operating parameters.

The device has an atrial sensing/pacing channel comprising ringelectrode 33 a, tip electrode 33 b, sense amplifier 31, pulse generator32, and an atrial channel interface 30 which communicatesbidirectionally with a port of microprocessor 10. The device also hastwo ventricular sensing/pacing channels that similarly include ringelectrodes 43 a and 53 a, tip electrodes 43 b and 53 b, sense amplifiers41 and 51, pulse generators 42 and 52, and ventricular channelinterfaces 40 and 50. For each channel, the electrodes are connected tothe pacemaker by a lead and used for both sensing and pacing. A MOSswitching network 70 controlled by the microprocessor is used to switchthe electrodes from the input of a sense amplifier to the output of apulse generator. The device also includes a shock pulse generator 90interfaced to the controller and a shock lead which incorporates a tipelectrode 93 b and a coil electrode 93 a. Coil electrodes can be used todeliver pacing pulses but are designed especially for deliveringcardioversion/defibrillation shocks. The shock lead would normally bedisposed in the right ventricle (RV) so that sensing or pacing of theventricles may be performed using tip electrode 93 b and/or coilelectrode 93 a. A ventricular cardioversion/defibrillation shock may bedelivered between coil 93 a and the can 60 when fibrillation or othertachyarrhythmia is detected. The device also has an evoked responsesensing channel that comprises an evoked response channel interface 20and a sense amplifier 21 that has its differential inputs connected to aselected electrode and to the device housing or can 60 through theswitching network 70. The evoked response sensing channel may be used toverify that a pacing pulse has achieved capture of the heart in aconventional manner or, as explained below, used to record an evokedresponse electrogram.

The channel interfaces include analog-to-digital converters fordigitizing sensing signal inputs from the sensing amplifiers, registersthat can be written to for adjusting the gain and threshold values ofthe sensing amplifiers, and, in the case of the ventricular and atrialchannel interfaces, registers for controlling the output of pacingpulses and/or adjusting the pacing pulse energy by changing the pulseamplitude or pulse width. The microprocessor 10 controls the overalloperation of the device in accordance with programmed instructionsstored in memory. The sensing circuitry of the device generates atrialand ventricular sense signals when voltages sensed by the electrodes(i.e., electrograms) exceed a specified threshold. The controller theninterprets sense signals from the sensing channels and controls thedelivery of paces in accordance with a programmed pacing mode. The sensesignals from any of the sensing channels of the pacemaker in FIG. 2 canbe digitized and recorded by the controller to constitute an electrogramthat can either be analyzed by the device itself or transmitted via thetelemetry link 80 to the external programmer 300.

The electrical response of the heart to a pacing pulse is referred to asan evoked response. If the evoked response indicates that a propagatingwave of depolarization has resulted from the pacing pulse, it evidencesthat the paced chamber has responded appropriately and contracted. Asdescribed herein, an electrogram can also be recorded of an evokedresponse to a pace and used to determine if a desired fusion beat hasoccurred. An evoked response sensing channel for recording anelectrogram can be a sensing channel normally used for other purposes orcan be a sensing channel dedicated to sensing evoked responses. In theembodiment illustrated in FIG. 2, a dedicated evoked response sensingchannel is provided where the differential inputs of sensing amplifier21 may be connected to a selected electrode and the can 60 by means ofswitch matrix 70. An electrogram signal for morphology analysis ispreferably obtained from a unipolar electrode with a large surface arearather than a conventional bipolar sensing/pacing electrode. It ispreferable for the evoked response sensing channel to employ unipolarsensing such that the sensing vector is between the unipolar electrodeand the device housing or can (or another distantly disposed electrodeor electrodes). A large unipolar electrode “sees” a larger volume of themyocardium, and changes in the depolarization pattern of the ventricleswill be more readily reflected in an electrogram generated by theelectrode during a ventricular beat. A convenient electrode for thispurpose is the coil electrode that the device normally uses fordelivering cardioversion/defibrillation shocks. An electrogram signalsuitable for morphology analysis may also be obtained by switching thededicated sensing channel to a subcutaneous electrode, referred to as asubcutaneous ECG channel. Since the switch matrix allows differentsensing vectors to be used for the optimization of AV and VV delays, itis desirable to select the most desirable sensing vectors for aparticular patient. One example selection method is to collect theelectrograms from different sensing vectors at several different AV andVV delays, extract the features, and choose the vectors which producethe maximum difference as the desired vector.

2. Example Algorithm for Optimal Adjustment of Programmed AV DelayInterval

FIG. 3 illustrates an exemplary algorithm for determining an optimum AVDinterval for delivering CRT to patients with intact native AVconduction. The algorithm may be performed by the controller of theimplantable device, by an external programmer in communication with theimplantable device, or by a clinician operating an external programmer.The implantable device is configured to deliver paces to both right andleft ventricles or to the left ventricle only in accordance with aprogrammed pacing mode, such that the pace or paces are delivered aftera programmed AV delay interval with respect to an atrial event. At stepS1, an evoked response electrogram is recorded during a paced cardiaccycle with a short AV delay interval expected to be shorter than thepatient's intrinsic atrioventricular interval. At step S2, the AV delayinterval is incremented by a predetermined amount, and at step S3another evoked response electrogram is recorded during a paced cardiaccycle with the incremented AV delay interval. At step S4, the evokedresponse electrograms recorded with the incremented and short AVDintervals are compared to determine if a sufficient difference ispresent to evidence occurrence of a fusion beat. Such a comparison maybe performed by cross-correlating the two electrogram waveforms andcomputing a correlation coefficient CC:

${CC} = \frac{\sum\limits_{i = 1}^{n}{x_{i} \cdot y_{i}}}{{\lbrack {\sum\limits_{i = 1}^{n}x_{i}^{2}} \rbrack^{1/2}\lbrack {\sum\limits_{i = 1}^{n}y_{i}^{2}} \rbrack}^{1/2}}$where x is the short AVD electrogram, y is the incremented AVDelectrogram, and n is the number of samples in the template. The valueCC is then compared with a specified threshold value to determine if thedifference between the two waveforms is sufficient to presume a fusionbeat has occurred. Alternatively, specific features may be extractedfrom the two waveforms and compared. If the difference between thefeatures extracted from each waveform exceeds a specified thresholdvalue, a fusion beat may be presumed to have occurred. If the differencebetween the short AVD electrogram and the incremented AVD electrogram issufficient, as tested for at step S5, the optimum AVD interval isdetermined to be the incremented AVD interval value at step S6.Otherwise, a return is made to step S2 where the AVD is incrementedagain by the predetermined amount until the evoked response electrogramrecorded with the incremented AV delay interval differs from the evokedresponse electrogram recorded with the short AV delay interval by thespecified threshold amount. The method may be performed to computeseparate optimum AV delay interval depending upon whether the atrialevent is an atrial sense or an atrial pace. The method may also beperformed to determine optimum AV delay intervals at a plurality ofdifferent pacing rates, with the optimum AV delay intervals asdetermined at the plurality of pacing rates used to form a mappingfunction (e.g., a look-up table or linear function) which mapsparticular pacing rates to particular programmed AV delay intervals. Themapping function may then be used to automatically adjust the programmedAV delay interval as the pacing rate changes.

Although not as common, some patients have a right ventricularconduction deficit such as right bundle branch block and requirepre-excitation of the right ventricle in order achieve synchronizationof their ventricular contractions. The preceding discussions havefocused primarily on the situation where one or more left ventricularsites are pre-excited with biventricular or left ventricle-only pacing.It should be appreciated that the techniques described herein could alsobe applied for optimally pre-exciting any late-contracting ventricularregion, including in the right ventricle. In those cases, the rightventricle is pre-excited with an optimized AVD delay interval usingeither biventricular or right ventricle-only pacing.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Such alternatives, variations, and modifications are intended to fallwithin the scope of the following appended claims.

1. A method for operating a cardiac rhythm management device in apatient, comprising: delivering pacing therapy in accordance with aprogrammed pacing mode for pre-exciting one of the ventricles relativeto the other ventricle, such that a pace to the pre-excited ventricle isdelivered after a programmed AV delay interval with respect to an atrialevent; and, determining an optimum AV delay interval by: recording anevoked response electrogram during a paced cardiac cycle with a short AVdelay interval expected to be shorter than the patient's intrinsicatrioventricular interval to ensure that paced excitation of bothventricles occurs before intrinsic activation; incrementing the AV delayinterval by a predetermined amount and recording an evoked responseelectrogram during a paced cardiac cycle with the incremented AV delayinterval; comparing the evoked response electrograms recorded with theincremented and short AV delay intervals; continuing to increment the AVdelay interval by the predetermined amount until the evoked responseelectrogram recorded with the incremented AV delay interval differs fromthe evoked response electrogram recorded with the short AV delayinterval by a specified amount so as to indicate the occurrence offusion beat that includes paced excitation of the pre-excited ventricleand intrinsic activation of the other ventricle; and, determining theoptimum AV delay interval as the incremented AV delay interval used whenthe fusion beat occurs.
 2. The method of claim 1 wherein the differencebetween the evoked response electrograms recorded with the short andincremented AV delay intervals is determined by performing across-correlation between the two electrograms and comparing a resultingcross-correlation coefficient to a specified threshold value.
 3. Themethod of claim 1 wherein the difference between the evoked responseelectrograms recorded with the short and incremented AV delay intervalsis determined by extracting a feature from each of the two electrogramsand comparing a difference between the extracted features with aspecified threshold value.
 4. The method of claim 1 further comprisingdetermining optimum AV delay intervals at a plurality of differentpacing pulse energies.
 5. The method of claim 1 further comprisingdetermining optimum AV delay intervals at a plurality of differentatrial rates.
 6. The method of claim 5 further comprising: using theoptimum AV delay intervals as determined at the plurality of atrialrates to form a mapping function which maps particular atrial rates toparticular programmed AV delay intervals; and, automatically adjustingthe programmed AV delay interval according to the mapping function asthe atrial rate changes.
 7. The method of claim 1 further comprisingdetermining a separate optimum AV delay interval depending upon whetherthe atrial event is an atrial sense or an atrial pace.
 8. The method ofclaim 1 further comprising determining an optimum VV delay interval forbiventricular pacing by: recording an evoked response electrogram duringa biventricular paced cardiac cycle with the determined optimum AV delayinterval with a short VV delay interval expected to be short enough toproduce biventricular capture; incrementing the VV delay interval by apredetermined amount and recording an evoked response electrogram duringa paced cardiac cycle with the incremented VV delay interval; comparingthe evoked response electrograms recorded with the incremented and shortVV delay intervals; and, continuing to increment the VV delay intervalby the predetermined amount until the evoked response electrogramrecorded with the incremented VV delay interval differs from the evokedresponse electrogram recorded with the short VV delay interval by aspecified amount.
 9. The method of claim 8 further comprisingdetermining optimum VV delay intervals for multiple pacing sites in theleft ventricle.
 10. The method of claim 1 further comprising selecting asensing vector for generating evoked response electrograms whichproduces the greatest morphology difference between electrograms offusion beats and electrograms of purely paced beats.
 11. A cardiacrhythm management device, comprising: one or more pulse generators fordelivering paces via pacing channels to both right and left ventricles;one or more sensing amplifiers for receiving an electrogram signal; acontroller programmed to deliver pacing therapy in accordance with aprogrammed pacing mode for pre-exciting one of the ventricles relativeto the other ventricle, such that a pace to the pre-excited ventricle isdelivered after a programmed AV delay interval with respect to an atrialevent; wherein the controller is programmed to determine an optimum AVdelay interval by: recording an evoked response electrogram during apaced cardiac cycle with a short AV delay interval which is expected tobe shorter than the patient's intrinsic atrioventricular interval;incrementing the AV delay interval by a predetermined amount andrecording an evoked response electrogram during a paced cardiac cyclewith the incremented AV delay interval; comparing the evoked responseelectrograms recorded with the incremented and short AV delay intervals;continuing to increment the AV delay interval by the predeterminedamount until the evoked response electrogram recorded with theincremented AV delay interval differs from the evoked responseelectrogram recorded with the short AV delay interval by a specifiedamount so as to indicate the occurrence of fusion beat that includespaced excitation of the pre-excited ventricle and intrinsic activationof the other ventricle; and, determining the optimum AV delay intervalas the incremented AV delay interval used when the fusion beat occurs.12. The device of claim 11 wherein the difference between the evokedresponse electrograms recorded with the short and incremented AV delayintervals is determined by performing a cross-correlation between thetwo electrograms and comparing a resulting cross-correlation coefficientto a specified threshold value.
 13. The device of claim 11 wherein thedifference between the evoked response electrograms recorded with theshort and incremented AV delay intervals is determined by extracting afeature from each of the two electrograms and comparing a differencebetween the extracted features with a specified threshold value.
 14. Thedevice of claim 11 wherein the controller is further programmed todetermine optimum AV delay intervals at a plurality of different pacingpulse energies.
 15. The device of claim 11 wherein the controller isfurther programmed to determine optimum AV delay intervals at aplurality of different atrial rates.
 16. The device of claim 15 whereinthe controller is further programmed to: use the optimum AV delayintervals as determined at the plurality of atrial rates to form amapping function which maps particular atrial rates to particularprogrammed AV delay intervals; and, automatically adjust the programmedAV delay interval according to the mapping function as the atrial ratechanges.
 17. The device of claim 11 wherein the controller is furtherprogrammed to determine a separate optimum AV delay interval dependingupon whether the atrial event is an atrial sense or an atrial pace. 18.The device of claim 11 wherein the controller is further programmed todetermine an optimum VV delay interval for biventricular pacing by:recording an evoked response electrogram during a biventricular pacedcardiac cycle with the determined optimum AV delay interval with a shortVV delay interval expected to be short enough to produce biventricularcapture; incrementing the VV delay interval by a predetermined amountand recording an evoked response electrogram during a paced cardiaccycle with the incremented VV delay interval; comparing the evokedresponse electrograms recorded with the incremented and short VV delayintervals; and, continuing to increment the VV delay interval by thepredetermined amount until the evoked response electrogram recorded withthe incremented VV delay interval differs from the evoked responseelectrogram recorded with the short VV delay interval by a specifiedamount.
 19. The device of claim 18 wherein the controller is furtherprogrammed to determine optimum VV delay intervals for multiple pacingsites in the left ventricle.
 20. The device of claim 11 wherein thecontroller is further programmed to select a sensing vector forgenerating evoked response electrograms which produces the greatestmorphology difference between electrograms of fusion beats andelectrograms of purely paced beats.